Systemic–local immune remodeling in colorectal cancer: CD14+ cell-derived cytokine responsiveness, mucosal immune-cell organization, and exploratory metastasis-associated patterns

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Background: Immune regulatory networks contribute to colorectal cancer (CRC) progression, but most clinical studies focus on tissue immune-cell abundance or static inflammatory mediators. We investigated cytokine-response patterns in cultures derived from peripheral-blood CD14+ cells and local immune-cell composition in tumor-adjacent and resection-margin mucosa. Methods: This single-center prospective observational study included 106 patients with colorectal adenocarcinoma and 20 comparison subjects with non-malignant surgical conditions. Peripheral-blood CD14+ cells were isolated, differentiated with M-CSF, and subjected to sequential LPS stimulation. IL-1β, IL-6, IL-8, and MCP-1 concentrations were measured, and cytokine-response indices were calculated. In CRC patients, CD4+, CD8+, CD20+, CD56+, and CD68+ cell densities were quantified immunohistochemically in paired mucosal compartments. Analyses addressed CRC-associated differences, local immune-cell organization, systemic-local associations, and an exploratory comparison between patients without distant metastases (n = 97) and patients with distant metastases (n = 9). Results: CRC was associated with selective remodeling of IL-1β and IL-6 response indices. Compared with the comparison group, CRC patients showed higher IL-1β post-washout persistence, lower shutdown efficiency and re-induction capacity, and a higher re-stimulation index. IL-6 responses were characterized by lower basal activity but higher basal drift, primary LPS response, and post-washout persistence. The exploratory comparison according to distant metastasis status identified additional differences in selected IL-1β and IL-6 indices, however, these findings are limited by the small number of patients with distant metastases. Locally, CD20+ cells were enriched in tumor-adjacent mucosa, whereas CD68+ cells were enriched in resection-margin mucosa. Matched immune-cell densities were positively correlated across compartments. The strongest systemic-local association was an inverse correlation between MCP-1 primary LPS response and CD68+ cell density in tumor-adjacent mucosa. Conclusions: CRC is associated with altered cytokine responsiveness in M-CSF-differentiated cultures derived from blood CD14+ cells and with compartment-specific mucosal immune-cell organization. The observed systemic-local associations suggest partial coupling between these experimental and tissue-level immune features. Exploratory metastasis-associated patterns were identified but require validation in larger, adequately powered cohorts.

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